cells Review Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder Jyoti Upadhyay 1, Jeevan Patra 1, Nidhi Tiwari 2, Nilima Salankar 3, Mohd Nazam Ansari 4,* and Wasim Ahmad 5 1 Department of Pharmaceutical Sciences, School of Health Sciences, University of Petroleum and Energy Studies, Energy Acre Campus Bidholi, Dehradun 248007, Uttarakhand, India; [email protected] (J.U.); [email protected] (J.P.) 2 Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organisation, Delhi 110054, India; [email protected] 3 School of Computer Sciences, University of Petroleum and Energy Studies, Energy Acre Campus Bidholi, Dehradun 248007, Uttarakhand, India; [email protected] 4 Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia 5 Department of Pharmacy, Mohammed Al-Mana College for Medical Sciences, Dammam 34222, Saudi Arabia; [email protected] * Correspondence: [email protected]; Tel.: +966-115-886-037 Abstract: Understanding the autistic brain and the involvement of genetic, non-genetic, and numer- ous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the Citation: Upadhyay, J.; Patra, J.; brain, autistic subjects show a few characteristics like impairment in social communications related to Tiwari, N.; Salankar, N.; Ansari, M.N.; repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused Ahmad, W. Dysregulation of Multiple by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD Signaling Neurodevelopmental subjects and genetic models revealed the involvement of mutated genes with alterations of numerous Pathways during Embryogenesis: A signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement Possible Cause of Autism Spectrum in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to Disorder. Cells 2021, 10, 958. https:// doi.org/10.3390/cells10040958 it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like “novel drugs Academic Editor: Stephen Yarwood for ASD” and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and Received: 20 March 2021 their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling Accepted: 19 April 2021 pathways, their significance, and implications for ASD. Published: 20 April 2021 Keywords: autism spectrum disorder; Asperger’s syndrome; neuropathological alterations; hedge- Publisher’s Note: MDPI stays neutral hog signaling pathway with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Autism Spectrum Disorder (ASD) is a chronic heterogeneous neurodevelopmental disorder characterized by impairment in social communications, related to restricted, Copyright: © 2021 by the authors. repetitive, or stereotypical behavior [1]. It is the principal cause of disability among Licensee MDPI, Basel, Switzerland. children less than 5 years of age suffering from mental disorders. It is more than conduct This article is an open access article disorder and ADHD (Attention Deficit Hyperactivity Disorder) together because it persists distributed under the terms and throughout the life span of children suffering from this disease [2]. It is a great challenge conditions of the Creative Commons for all developing countries, especially India, because of the severity of this disorder and its Attribution (CC BY) license (https:// influence on the affected children and their families including the economic burden which creativecommons.org/licenses/by/ 4.0/). imposes on the parents coupled with lack of knowledge about the disorder [3]. A lack Cells 2021, 10, 958. https://doi.org/10.3390/cells10040958 https://www.mdpi.com/journal/cells Cells 2021, 10, 958 2 of 20 of knowledge and awareness, wrong diagnosis, and inclusion of autism disorder under the normal classification of intellectual disability, language, or speech disorders are most commonly observed [4]. Some previous research studies suggested that early detection and intervention can improve language and speech abilities as well as reduce cognitive decline and behavior in affected children [5]. They also supported the idea that ASD can be diagnosed in the first two years after birth [6]; however, several studies report that a substantial proportion of affected children are not diagnosed until they are school-aged [7]. Worldwide data collected by survey analysis and routine monitoring structures show that several countries since the 1990s have identified an estimated rise in the prevalence of ASD from 0.7 to 1.0% [7]. The Centers for Disease Control and Prevention (CDC) in the United States conducted a study and reported that, from 11 sites, 1 in 54 children suffer from ASD, indicating an elevation in cases over the past two decades [8]. ASD prevalence in Asian countries has also been estimated, and it was found that in India, 1.7 to 2 million individuals are affected with ASD [9,10]. These rises in the number of ASD cases in the Indian population have increased the need to consider associated risk factors as well as to discover early detection techniques and therapeutic interventions. Autism disorder was first identified in 1943 by Kanner in 11 children with similar symptoms like impaired speech and language, obsessive behavior, and deficits in social cognition. An epidemiological study on autism was conducted 23 years afterwards and estimated a prevalence rate of 4.5 per 10,000 persons. This estimated ratio was drastically increased to 1 in 59 persons, with males being diagnosed three times more than females [11]. This elevation in prevalence is the result of an increase in knowledge and awareness and an advancement in the Diagnostic and Statistical Manual of Mental Disorder (DSM) standards, which covers a broad range of disorders [12]. The etiology of ASD remains a topic of debate: Its origin, genetic and environmental factors, and their interplay form a range of cognitive, behavioral, and developmental features observed in affected individuals. The main aim of this review is to identify the etiological factors and pathogenesis and to characterize the methodological features together with recent therapeutic interventions. Unlocking the etiology of these multifaceted developmental disorders requires a collaborative research discipline including health care professionals, environmental experts, geneticists, bioinformaticians, and computer scientists. 2. Types of Autism Spectrum Disorder ASD involves Asperger’s syndrome, autistic disorders, pervasive developmental disorders not otherwise specified (PDD-NOS), and Rett syndrome [13]. Asperger’s syn- drome was identified in 1940 by pediatrician Hans Asperger. He observed symptoms of autism-like difficulty in communication and social interaction in boys with normal language development and intelligence. Many healthcare professionals have suggested that Asperger’s is a minor form of ASD and specified the term “high-functioning autism” to describe children affected with it [14]. The Diagnostic and Statistical Manual of Mental Disorders (DSM) is the standard guideline used by psychiatrists and physicians in the United States to diagnose any type of mental illnesses. In DSM-V diagnostic criteria for ASD, patients have persistent deficits in three areas of social interaction and communication: social-emotional reciprocity; non- verbal communicative behaviors; and maintaining, understanding, developing relation- ships. It also includes four types of restricted and repetitive behaviors: stereotypical repetitive motor movements, insistence or sameness, highly restricted or fixated interest, and hyper- or hypo-reactivity to sensory signals [15]. Without a diagnosis, PDD-NOS in children shows manifestations like restricted com- munications (verbal and non-verbal), social, and stereotypical behavior. Some epidemiolog- ical studies suggested that PDD-NOS are twice as common as autism [16]. The diagnostic features associated with PDD-NOS are (i) onset of this disease after 3 years of age, (ii) atypical symptoms, and (iii) Fewer than six criteria and their subthresholds [7,17]. A research study showed that children suffering from PDD-NOS were initially diagnosed Cells 2021, 10, 958 3 of 20 with Attention Deficit Hyperactivity Disorder (ADHD) and that they did not differ from ADHD children with respect to all the symptoms of ASD, attention difficulties, or general psychopathology. No method has yet been established for differentiating ADHD and PDD-NOS [18]. Table1 indicates the three severity levels of ASD. Table 1. Three severity levels of ASD (modified from American Psychiatric Association, 2013) [13]. Clinical Symptoms Levels Social Communication Repetitive Behavior Severe impairment in verbal and non-verbal Rigid behavior; extreme problems coping communication; a deficit in social with change; repetitive or restricted Requires extensive interactions; less response to social overtures Level 1 behavior marked by interferences